Allergic diseases are caused by skewed immune responses to otherwise harmless antigens, and, in one form or another, affect up to 25% of the population in the United States, with a disproportionately increase especially among children with asthma and food-related hypersensitivities. The binding of specific IgE to cells bearing high affinity receptors (Fc?RI) is hallmark for the pathogenesis of allergic disease in that subsequent interaction with allergen causes cells such as basophils, mast cells, and dendritic cells to release pro-inflammatory mediators and cytokines that promote and/or amplify disease. In particular, crosslinking of IgE/Fc?RI triggers basophils to release histamine and LTC4 but also IL-4 and IL-13 ? mediators and cytokines central to the allergic diathesis. More recently, these activities have been confirmed and extended in vivo using mouse models, with some showing evidence for an ?axis? whereby epithelial cell (EC)-derived cytokines activate basophils to produce IL-4 (& IL-13). In contrast, confirmatory results of these EC cytokines activating human basophils have not been forthcoming. In exploring this translational discrepancy, we serendipitously uncovered a remarkably robust, and potentially unique, mode of EC-dependent activation of human basophils that requires cell-to-cell adhesion and is IgE-dependent. Preliminary data now point to this mode of activation (discovered after co-culturing basophils with A549-lung EC) as being mediated by galectin-3 (Gal-3) ?a lectin long known to bind IgE. There is also rationale for yet another level of regulation to this response ?one mediated by Gal-9, which also binds IgE with nearly 100- fold greater affinity than does Gal-3 but lacks IgE/Fc?RI crosslinking capabilities. Aim 1 studies further characterize the parameters underlying EC-dependent activation of basophils, with the goal of extending Gal-3-dependent activation to include primary human epithelial cells (PHEC). The Gal-3/Gal-9 interplay is also to be addressed in PHEC using genetic manipulation as well as a model whereby microspheres are coated with these galectins. Signaling pathways will also be explored and are thought to differ from those associated with standard anaphylactic release. Aim 2 will test the hypothesis that Gal-3/9 interplay also regulates the activities of other IgE-bearing cells, with preliminary evidence that Gal-3 also induces DC subtypes to secrete large quantities of pro-inflammatory cytokines (i.e. TNF-?/IL-6). Finally, Aim-3 investigates the regulation of Gal3/9 on EC, hypothesizing that their expression is counter-regulated by pro- inflammatory cytokines/mediators vs. innate immune stimuli. Overall, these results could ultimately provide insight into several unexplained IgE-related phenomena for which these IgE-bearing cells and Gal-3 are all implicated, ranging from allergic disease (e.g. asthma, chronic urticaria, and atopic dermatitis) to non- allergic conditions, including autoimmunity (lupus nephritis), cancer, and conceivably wound healing.